Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis C virus (HCV) has been reported to elicit B and T cell immunity in infected patients. Despite the presence of antiviral immunity, many patients develop chronic infections leading to cirrhosis, hepatocellular carcinoma, and liver failure that can require transplantation. We have previously described the presence of HLA-A2-restricted, HCV NS3-reactive cytotoxic T lymphocytes (CTL) in the blood of HLA-A2- liver transplantation patients that received an HLA-A2+ liver allograft. These T cells are analogous to the "allospecific" T cells that have been described in hematopoietic stem cell transplantation patients. It has been speculated that allospecific T cells express high-affinity T cell receptors (TCRs). To determine if our HCV-reactive T cells expressed TCRs with relatively high affinity for antigen, we identified and cloned a TCR from an allospecific HLA-A2-restricted, HCV:NS3:1406-1415-reactive CD8+ T cell clone and expressed this HCV TCR in Jurkat cells. Tetramer binding to HCV TCR-transduced Jurkat cells required CD8 expression, whereas antigen recognition did not. In conclusion, based on the reactivity of the TCR-transduced Jurkat cells, we have identified a TCR that transfers anti-HCV reactivity to alternate effectors. These data suggest this high affinity HCV-specific TCR might have potential new immunotherapic implications.
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PMID:Identification of a hepatitis C virus-reactive T cell receptor that does not require CD8 for target cell recognition. 1662 27

HCV (hepatitis C virus) has a high propensity to persist and to cause chronic hepatitis C, eventually leading to cirrhosis. Since HCV itself is not cytopathic, liver damage in chronic hepatitis C is commonly attributed to immune-mediated mechanisms. HCV proteins interact with several pathways in the host's immune response and disrupt pathogen-associated pattern recognition pathways, interfere with cellular immunoregulation via CD81 binding and subvert the activity of NK (natural killer) cells as well as CD4(+) and CD8(+) T-cells. Finally, HCV-specific T-cells become increasingly unresponsive and apparently disappear, owing to several possible mechanisms, such as escape mutations in critical viral epitopes, lack of sufficient help, clonal anergy or expansion of regulatory T-cells. The role of neutralizing antibodies remains uncertain, although it is still possible that humoral immunity contributes to bystander damage of virally coated cells via antibody-dependent cellular cytotoxicity. Cytotoxic lymphocytes kill HCV-infected cells via the perforin/granzyme pathway, but also release Fas ligand and inflammatory cytokines such as IFNgamma (interferon gamma). Release of soluble effector molecules helps to control HCV infection, but may also destroy uninfected liver cells and can attract further lymphocytes without HCV specificity to invade the liver. Bystander damage of these non-specific inflammatory cells will expand the tissue damage triggered by HCV infection and ultimately activate fibrogenesis. A clear understanding of these processes will eventually help to develop novel treatment strategies for HCV liver disease, independent from direct inhibition of HCV replication.
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PMID:Immunopathogenesis in hepatitis C virus cirrhosis. 1719 58

Both hepatitis B virus (HBV) and hepatitis C virus (HCV) can cause persistent viral infection in humans. Chronic infection is associated with a risk of cirrhosis and hepatocellular carcinoma. The cause of chronic infection is unknown. A large body of evidence suggests that a failure of the adaptive immune response is critical in the establishment of chronic infection. Recently a new group of T cells (T-regulatory cells), that express CD4(+)CD25(+) and Foxp3, which can inhibit the cellular (CD4(+)/CD8(+)) immune response have been described. In this review the authors explore the thoughts regarding immune responses to HBV and HCV infections and the role of these T-regulatory cells in relation to the pathogenesis of chronic HBV and HCV infection and the potential for therapeutic intervention.
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PMID:T-regulatory lymphocytes and chronic viral hepatitis. 1796 Oct 92

More than 500 million people worldwide are persistently infected with hepatitis B virus or hepatitis C virus. Although both viruses are poorly cytopathic, persistence of either virus carries a risk of chronic liver inflammation, potentially resulting in liver steatosis, liver cirrhosis, end-stage liver failure or hepatocellular carcinoma. Virus-specific T cells are a major determinant of the outcome of hepatitis, as they contribute to the early control of chronic hepatitis viruses, but they also mediate immunopathology during persistent virus infection. We have analyzed the role of platelet-derived vasoactive serotonin during virus-induced CD8(+) T cell-dependent immunopathological hepatitis in mice infected with the noncytopathic lymphocytic choriomeningitis virus. After virus infection, platelets were recruited to the liver, and their activation correlated with severely reduced sinusoidal microcirculation, delayed virus elimination and increased immunopathological liver cell damage. Lack of platelet-derived serotonin in serotonin-deficient mice normalized hepatic microcirculatory dysfunction, accelerated virus clearance in the liver and reduced CD8(+) T cell-dependent liver cell damage. In keeping with these observations, serotonin treatment of infected mice delayed entry of activated CD8(+) T cells into the liver, delayed virus control and aggravated immunopathological hepatitis. Thus, vasoactive serotonin supports virus persistence in the liver and aggravates virus-induced immunopathology.
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PMID:Aggravation of viral hepatitis by platelet-derived serotonin. 1915 26

Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver characterized by progressive bile duct destruction eventually leading to cirrhosis and liver failure. The serological hallmark of the disease is the presence of circulating antimitochondrial antibodies (AMA). These reflect the presence of autoreactive T and B cells to the culprit antigens, the E2 subunits of mitochondrial 2-oxo-acid dehydrogenase enzymes, chiefly pyruvate dehydrogenase (PDC-E2). The disease results from a combination of genetic and environmental risk factors. Genetic predisposition is indicated by the higher familial incidence of the disease particularly among siblings and the high concordance rate among monozygotic twins. Environmental triggering events appear crucial to disrupt a pre-existing unstable immune tolerance of genetic origin allowing, after a long latency, the emergence of clinical disease. Initiating mimetopes of the vulnerable epitope of the PDC-E2 autoantigen can be derived from microbes that utilize the PDC enzyme or, alternatively, environmental xenobiotics/chemical compounds that modify the structure of native proteins to make them immunogenic. A further alternative as a source of antigen is PDC-E2 derived from apoptotic cells. In the effector phase the biliary ductular cell, by reason of its proclivity to express the antigen PDC-E2 in the course of apoptosis, undergoes a multilineage immune attack comprised of CD4(+) and CD8(+) T cells and antibody. In this article, we critically review the available evidence on etiopathogenesis of PBC and present interpretations of complex data, new developments and theories, and nominate directions for future research.
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PMID:Etiopathogenesis of primary biliary cirrhosis. 1852 30

Hepatitis C virus (HCV) becomes chronic in about 85 % of infected individuals, whereas only 15 % of infected people clear spontaneously the virus. The progression of hepatitis C to chronic status is associated to a profound down-regulation of CD4 and CD8 multispecific immune response. This immune defect may participate to the immune tolerance of VHC and consequently to its persistence. Recent findings indicate that T regulatory cells as Tr1 play an inhibitory role on T helper responses notably in the context of auto-immune or inflammatory disorders. The existence of immunosuppressive mechanisms supported by Tr1 lymphocytes and their IL-10 production represent an attractive hypothesis. We have previously evaluated the existence of regulatory T cells (Tr1) via high production of IL-10, in liver biopsies of three well-defined cohorts of HCV-1b infected patients. To this purpose, we compared liver biopsies of chronically infected patients including patients without liver lesions, with cirrhosis and with hepatocellular carcinoma (HCC). Using quantitative real time PCR, the results obtained demonstrate, an increased expression of interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta)_, in liver biopsies with more severe fibrosis. This observation was correlated with an increased expression during the pathogenesis progression, of the three specific markers of the Tr1 cells sub-population, recently described and confirming the Tr1 phenotype. Evidence of regulatory T cells installation in the liver of chronically infected patient and increased frequency in cirrhosis and HCC suggest a main role of these cells in the aggravation of the liver pathology. This study should bring insight of T regulatory cell implications in VHC persistence and in the pathology progression.
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PMID:[Role of the Regulatory T lymphocytes in hepatitis C fibrosis progression]. 1903 74

More than 500 million people worldwide are persistently infected with hepatitis B virus or hepatitis C virus. Although both viruses are poorly cytopathic, persistence of either virus carries a risk of chronic liver inflammation, potentially resulting in liver steatosis, liver cirrhosis, end-stage liver failure or hepatocellular carcinoma. Virus-specific T cells are a major determinant of the outcome of hepatitis, as they contribute to the early control of chronic hepatitis viruses, but they also mediate immunopathology during persistent virus infection. We have analyzed the role of platelet-derived vasoactive serotonin during virus-induced CD8(+) T cell-dependent immunopathological hepatitis in mice infected with the noncytopathic lymphocytic choriomeningitis virus. After virus infection, platelets were recruited to the liver, and their activation correlated with severely reduced sinusoidal microcirculation, delayed virus elimination and increased immunopathological liver cell damage. Lack of platelet-derived serotonin in serotonin-deficient mice normalized hepatic microcirculatory dysfunction, accelerated virus clearance in the liver and reduced CD8(+) T cell-dependent liver cell damage. In keeping with these observations, serotonin treatment of infected mice delayed entry of activated CD8(+) T cells into the liver, delayed virus control and aggravated immunopathological hepatitis. Thus, vasoactive serotonin supports virus persistence in the liver and aggravates virus-induced immunopathology.
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PMID:Hepatic microcirculation: a critical but neglected factor for the outcome of viral hepatitis. 1954 27

Aging is associated with a complex remodeling of the immune system. While adaptive immune responses show impairment with aging, innate immune responses tend to improve it. Low numbers of CD3+, CD4+ and CD8 T cells have been observed in aged individuals. B lymphocytes tend to diminish as well. However, an increase in NK cells and effector T lymphocytes (CD28- CD8) can be shown. Effector T lymphocytes are characterized by: 1) expression of markers of cytotoxicity; 2) high levels of NK activity; 3) expression of the same inhibitory receptors as NK cells; 4) no cytokine production. For effector T lymphocyte-mediated cytotoxicity of virus-infected cells to occur, viral epitopes need to be exposed on the cell surface in the absence of MCH class I molecule expression, just as it has been shown with NK cells. Indeed, chronic infection with intracellular parasites is known to hinder MHC class I expression on cell surface. In elderly patients with chronic hepatitis C, infected hepatocytes can be shown to express a wide variety of HCV antigens, reflecting latency or active replication, as opposed to low or absent MHC class I expression. This favors elimination of infected hepatocytes by NK cells and effector T lymphocytes. A negative correlation has been observed between outcome of hepatitis and patients' age. Liver biopsies from elderly patients generally show chronic active hepatitis or cirrhosis, which are far less commonly observed in young patients or young adults. Overproduction of proinflammatory cytokines, namely TNF-alpha, IL-1 and IL-6, is responsible for enhanced immuno-phlogosis and underlies a more extensive damage to liver parenchyma. Since interferon-alpha has been shown to upregulate MHC class I molecule expression on infected hepatocytes, it may turn useful as a tool to inhibit NK cell- and effector T lymphocyte-mediated cytotoxicity. Thus, a rationale exists to recommend interferon-a administration in hepatitis C patients, especially in elderly patients. If the data presented here can contribute to foster research into interferon-a treatment of elderly patients with hepatitis C, our goal will be reached.
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PMID:Chronic hepatitis C in the advanced adult and elderly subjects. 1930 74

Although many studies on the risk factors and their carcinogenesis in adult hepatocellular carcinoma (HCC) have been reported, they remain poorly understood in childhood HCC. A retrospective study of 42 HCC cases in Asian children was conducted. Hepatitis B virus (HBV)-DNA in HCC tissues was detected in 36 of 42 (86%) cases tested, while no hepatitis C virus (HCV)-RNA was detectable in any of HCCs. Twenty of 36 (56%) HCC cases were accompanied by cirrhosis. Surprisingly, very high prevalence of the HBV pre-S deletion mutant was recognized in 27 of 30 (90%) HCCs examined. They occurred most frequently in pre-S2 (20/27, 74%) followed by pre-S1 (5/27, 18.5%), and both pre-S1/S2 (2/27, 7.4%). Interestingly, the pre-S2 mutant consistently appeared with deletion at nt 4-57 in all of the 20 cases with the pre-S2 mutant (100%) and within this locus in the two cases with both pre-S-1/S2 mutants. Type II ground-glass hepatocytes in non-tumorous livers were seen in 15 of the 22 HCCs with the pre-S2 deletion mutant (68%). This hotspot mutation in the pre-S2 was further confirmed by complete genomic sequence of HBV in a Japanese boy who eventually developed HCC. Our result strongly suggests that HBV is a major contributor to the development of HCC in Asian children. The HBV pre-S2 deletion mutant at nt 4-57 which has a CD8 T-cell epitope could be responsible for the emergence and aggressive outcome of childhood HCC. Determination of this hotspot mutation in the pre-S2 region could be a useful index for predicting the clinical outcome of HCC development.
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PMID:Pre-S2 deletion mutants of hepatitis B virus could have an important role in hepatocarcinogenesis in Asian children. 1971 72

The objectives of this work were the analysis of the functional characteristics of circulating monocytes and T lymphocytes in patients with liver cirrhosis, and evaluation of the relationship with an increased exposure to antigens due to bacterial translocation. Forty patients with liver cirrhosis (20 with compensated cirrhosis and 20 with ascitic decompensation) and 20 healthy control subjects were studied. Bacterial translocation was evaluated by serum levels of lipopolysaccharide binding protein (LBP). Macrophage activation was studied by CD40 antigen expression. T lymphocytes were analysed for activation (CD25(+), CD122(+)), effector function (CD8(+)CD45RO(+)CD57(+)), apoptosis (CD95(+)) and regulatory abilities, either by analysis of the membrane expression of co-stimulatory molecules CD80, CD86 and CD28, or by quantification of regulatory T cells CD4(+)CD25(high)forkhead box P3 (FoxP3). The percentage of activated monocytes and T lymphocytes in patients was increased significantly. The proportions of effector senescent cells and of those near to apoptosis were also significantly higher. With respect to these proportions, there were no significant differences between patients in function of the presence or absence of decompensation or in function of the increased or normal values of LBP. Conversely, those patients with elevated levels of LBP presented a significantly higher frequency of regulatory T cells than those with normal levels. In conclusion, patients with liver cirrhosis showed an intensive activation state with a higher percentage of cells committed to activation-induced death, even in non-advanced stages. It is possible that bacterial permeability and endotoxaemia contribute to the expansion of those lymphocyte populations implicated in the prevention of a more severe antigen-induced immunopathology.
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PMID:Chronic antigenic stimuli as a possible explanation for the immunodepression caused by liver cirrhosis. 1973 42


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